Clinical trial • Phase II • Rare Disease

ALPELISIB for PIK3CA-related overgrowth spectrum (PROS)

Phase II trial of ALPELISIB for PIK3CA-related overgrowth spectrum (PROS). open-label. 32 participants.

Overview

Trial Therapeutic Area
Rare Disease
Trial Disease
PIK3CA-related overgrowth spectrum (PROS)
Trial Stage
Phase II
Drug Modality
Small molecule
Paediatric Trial
Yes
Orphan Drug
Yes

Key dates

Initial CTIS Submission Date
27-06-2025
First CTIS Authorization Date
20-10-2025

Trial design

open-label Phase II trial across 29 sites in Italy, Spain, Germany and others.

Open Label
Yes
Target Sample Size
32
Trial Duration For Participant
168

Eligibility

Recruits 32 paediatric patients.

Vulnerable Population
Pediatric participants are included (aged ≥2 years). For minors, informed consent is obtained from the parent/legal guardian and assent is obtained from children/adolescents as applicable. Age-specific informed consent and assent documents (Parent Legal Guardian, Adolescent Assent, Child Assent) are provided in country-specific submission packages.

Inclusion criteria

  • {"criterion_text":"- Male or female participants aged ≥2 years at the time of informed consent/assent.\n- Participants with diagnosis of PROS (according to Clinical Diagnostic Criteria for PROS proposed by Keppler-Noreuil et al 2014) with symptomatic AND progressive overgrowth, who have syndromic disease or isolated features (with the exception of isolated macrodactyly, macrocephaly or epidermal nevus) at the time of informed consent/assent.\n- Documented evidence of a somatic mutation(s) in the PIK3CA gene performed in local laboratories using a DNA-based test AND available archival tissue (if archival tissue sample is not available, a fresh biopsy should be performed, if it is not clinically contraindicated) at the time of informed consent/assent.\n- Karnofsky (in participants >16 years of age at study entry) or Lansky (≤16 years of age at study entry) performance status index ≥50.\n- PGI-S score of mild, moderate, severe, or very severe at screening\n- Adequate bone marrow and organ function.\n- Presence of at least 1 PROS-related measurable lesion (longest diameter ≥2 cm) confirmed by BIRC assessment and associated with complaints, clinical symptoms or functional limitations affecting the participant's everyday life."}

Exclusion criteria

  • {"criterion_text":"- Participant with only isolated macrodactyly, epidermal nevus/nevi and macroencephaly (the only clinical feature or a combination of any of three of them), in absence of other PROS-related lesions at the time of informed consent/assent\n- Previous treatment with alpelisib and/or any other phosphatidylinositol 3-kinase (PI3K) inhibitor(s) (except treatment attempt, defined as the attempt to treat PROS with any of PI3K inhibitors, with treatment duration less than 2 weeks and stopped at least 4 weeks prior to the first dose of study medication with alpelisib).\n- Debulking or other major surgery performed within 3 months at the time of informed consent/assent.\n- Radiation exposure for PROS treatment purpose within 12 months prior to informed consent/assent.\n- Clinically meaningful PROS-related thrombotic event (Grade 2 and more as per CTCAE v4.03) within 30 days before informed consent/assent, and/or sclerotherapy/embolization for vascular complications performed within 6 weeks before informed consent/assent.\n- Clinically meaningful bleeding from PROS-related lesion (Grade 2 and more as per CTCAE v4.03) within 30 days before study treatment initiation.\n- Participants with clinically significant worsening of PROS-related laboratory abnormalities, physical signs and symptoms (such as, but not limited to increase of D-dimers, worsening of underlying pain, newly occurring swelling or redness) indicating an uncontrolled condition during the screening phase."}

Endpoints

Primary endpoints

  • {"endpoint_text":"- Proportion of participants achieving confirmed objective response at any time, defined as achieving radiological response confirmed by a subsequent assessment performed at least after 4 weeks.","definition_or_measurement_approach":"Confirmed objective response defined as achieving radiological response confirmed by a subsequent assessment performed at least after 4 weeks."}

Secondary endpoints

  • {"endpoint_text":"- Changes from baseline in PROS lesion volumes(as assessed by BIRC) in the: • Sum of target lesion volume. • Sum of MRI-measurable non-target lesion volume. • Sum of all MRI-measurable (target and nontarget)lesion volume. Change from baseline in other non-target lesions(by BIRC). Appearance of new lesions (by BIRC).","definition_or_measurement_approach":"Lesion volume changes assessed by BIRC (Blinded Independent Review Committee) including sum of target lesion volume, sum of MRI-measurable non-target lesion volume, and sum of all MRI-measurable lesion volume; appearance of new lesions assessed by BIRC."}
  • {"endpoint_text":"- Proportion of participants with a radiological response at scheduled protocol timepoints","definition_or_measurement_approach":"Radiological response assessed at scheduled protocol timepoints (see protocol Section 8.3.3 for definition)."}
  • {"endpoint_text":"- Duration of response defined as the time from the first documented confirmed objective response until progression of any PROS lesion (by BIRC) or death due to any cause or rescue surgery for any PROS lesion, whichever comes first","definition_or_measurement_approach":"Duration measured from first documented confirmed objective response until PROS lesion progression per BIRC, death, or rescue surgery (whichever occurs first)."}
  • {"endpoint_text":"- Alpelisib plasma concentration at selected time points.","definition_or_measurement_approach":"Pharmacokinetic measurement: alpelisib plasma concentrations measured at protocol-specified time points."}
  • {"endpoint_text":"- Change in scores from Brief Pain Inventory (BPI) items, or Wong-Baker Faces Scale (age appropriate), and Patient Global Impression of Symptom Severity (PGI-S).","definition_or_measurement_approach":"Patient-reported outcomes assessed by BPI items, age-appropriate Wong-Baker Faces Scale, and PGI-S with changes from baseline recorded."}
  • {"endpoint_text":"- Time to treatment failure (TTF) is defined as the time from alpelisib treatment start date until disease progression confirmed by BIRC, death, rescue surgery for any PROS lesion or discontinuation of the study treatment due to any reason other than technical problems or study termination by the sponsor.","definition_or_measurement_approach":"TTF measured from treatment start to BIRC-confirmed progression, death, rescue surgery, or treatment discontinuation for reasons other than technical problems or sponsor study termination."}
  • {"endpoint_text":"- Overall clinical response as assessed by Investigator","definition_or_measurement_approach":"Clinical response assessed by investigator at scheduled visits (see protocol for assessment criteria)."}
  • {"endpoint_text":"- Change from baseline in PROS-related symptoms and in complications/comorbidities among participants with symptoms and complications/comorbidities present at baseline.","definition_or_measurement_approach":"Changes from baseline in PROS-related symptoms and complications/comorbidities measured per protocol assessments."}
  • {"endpoint_text":"- Number/percentage of participants with healthcare visits/hospitalized due to PROS; number of hospitalizations. Number/percentage of participants with surgeries required to manage PROS; number of surgeries.","definition_or_measurement_approach":"Counts and percentages of participants with PROS-related healthcare visits/hospitalizations and surgeries; number of events recorded."}
  • {"endpoint_text":"- Incidence, type and severity of treatment-emergent adverse events per CTCAE v4.03 criteria and other safety data including changes in laboratory values, vital signs, assessments of cardiac function, growth, bone/dental development and sexual maturation (for applicable age).","definition_or_measurement_approach":"Safety assessed by incidence, type and severity of TEAEs per CTCAE v4.03 and other safety measures including labs, vitals, cardiac assessments and age-appropriate growth/development evaluations."}

Recruitment

Planned Sample Size
32
Recruitment Window Months
59
Consent Approach
Adult participants provide informed consent. For minors (≥2 to <18 years) consent is obtained from the parent/legal guardian and assent from children/adolescents as applicable. Age-specific ICFs and assent forms (Parent Legal Guardian, Adolescent Assent, Child Assent) are provided. Documents are available in multiple languages across country submissions (examples include English, Spanish, Italian, German, French, Dutch).

Methods

  • Country-specific recruitment arrangements (K1 documents) submitted for each Member State (K1 documents present for IT, ES, DE, AT, BE, FR, NL).
  • Use of advertisements (K2_Advertisements documents) for recruitment (K2 documents present for multiple countries).
  • Patient recruitment and retention tools provided by Jumo Health USA Inc. (duty listed: Patient recruitment and retention tools).
  • Patient expense (travel, lodging) reimbursement arranged via Scout Clinical (duty listed: Patient expense (travel, lodging) reimbursement).

Geography

Total Number Of Sites
29
Total Number Of Participants
72

Italy

Earliest CTIS Part Ii Submission Date
07-10-2025
Latest Decision Or Authorization Date
16-04-2026
Processing Time Days
191
Number Of Sites
3
Number Of Participants
8

Sites

Site Name
Fondazione Policlinico Universitario Agostino Gemelli IRCCS
Department Name
1301: UOSA Malattie Rare di Transizione Dip. Salute della Donna del Bambino e Sanità Pubblica
Contact Person Name
Chiara LEONI
Site Name
Azienda Ospedaliera Universitaria Citta Della Salute E Della Scienza Di Torino
Department Name
1300: S.C. Pediatria Specialistica Universitaria
Contact Person Name
Alessandro MUSSA
Contact Person Email
alessandro.mussa@unito.it
Site Name
Istituto Di Ricovero E Cura A Carattere Scientifico Materno Infantile Burlo Garofolo
Department Name
1302: Unità malattie metaboliche e rare
Contact Person Name
Irene BRUNO
Contact Person Email
irene.bruno@burlo.trieste.it

Spain

Earliest CTIS Part Ii Submission Date
18-09-2025
Latest Decision Or Authorization Date
20-04-2026
Processing Time Days
214
Number Of Sites
4
Number Of Participants
14

Sites

Site Name
Hospital Sant Joan De Deu Barcelona
Department Name
1501: Dermatología
Contact Person Name
Eulalia Baselga Torres
Contact Person Email
eulalia.baselga@sjd.es
Site Name
Complexo Hospitalario Universitario A Coruna
Department Name
1503: Cirugía Plástica
Contact Person Name
Manuel Gómez Tellado
Contact Person Email
manuel.gomez.tellado@sergas.es
Site Name
Hospital Universitari Vall D Hebron
Department Name
1502: Oncología
Contact Person Name
Marina Ortiz Palacios
Contact Person Email
marina.ortiz@vallhebron.cat
Site Name
Hospital Universitario La Paz
Department Name
1500: Cirugía Plástica
Contact Person Name
Juan Carlos López Gutiérrez

Germany

Earliest CTIS Part Ii Submission Date
18-09-2025
Latest Decision Or Authorization Date
15-04-2026
Processing Time Days
209
Number Of Sites
8
Number Of Participants
16

Sites

Site Name
Katholisches Kinderkrankenhaus Wilhelmstift gGmbH
Department Name
#1203: Abteilungen für Pädiatrie und Pädiatrische Dermatologie
Contact Person Name
Peter Höger
Contact Person Email
P.Hoeger@KKH-Wilhelmstift.de
Site Name
Charite Universitaetsmedizin Berlin KöR
Department Name
#1207: Klinik für Pädiatrie mit Schwerpunkt Hämatologie/ Onkologie
Contact Person Name
Susanne Holzhauer
Contact Person Email
Susanne.holzhauer@charite.de
Site Name
Universitaetsklinikum Halle (Saale) AöR
Department Name
#1202: Klinik und Poliklinik fuer Paediatrie I
Contact Person Name
Simone Hettmer
Contact Person Email
Simone.Hettmer@uk-halle.de
Site Name
Universitaetsklinikum Leipzig AöR
Department Name
#1206: Abteilung fuer Frauen-und KindermedizinPaediatrische Onkologie
Contact Person Name
Susanne Wendt
Site Name
Universitaetsklinikum Duesseldorf AöR
Department Name
#1200: Klinik f Kinder-Onkologie, Haematologie und Klinische Immunologie
Contact Person Name
Florian Babor
Site Name
Medical Center - University Of Freiburg
Department Name
#1204: Kinder- und Jugendklinik
Contact Person Name
Friedrich Kapp
Site Name
Klinikum Der Landeshauptstadt Stuttgart gKAöR
Department Name
#1201: Pädiatrie 5 (Onkologie, Hämatologie, Immunologie)
Contact Person Name
Claudia Blattmann
Site Name
Universitaetsklinikum Heidelberg AöR
Department Name
#1205: pädiatrisches Klinisch-Pharmakologisches Studienzentrum (paedKliPS)
Contact Person Name
Steffen Syrbe

Austria

Earliest CTIS Part Ii Submission Date
19-09-2025
Latest Decision Or Authorization Date
17-04-2026
Processing Time Days
210
Number Of Sites
2
Number Of Participants
2

Sites

Site Name
St. Anna Kinderspital GmbH
Department Name
#1800: Hämatologie und Onkologie
Contact Person Name
Leo Kager
Contact Person Email
Leo.kager@stanna.at
Site Name
Gemeinnuetzige Salzburger Landeskliniken Betriebsgesellschaft mbH
Department Name
#1801: Kinder- und Jugendchirurgie
Contact Person Name
Armin-Johannes Michel
Contact Person Email
a.michel@salk.at

Belgium

Earliest CTIS Part Ii Submission Date
19-09-2025
Latest Decision Or Authorization Date
16-04-2026
Processing Time Days
209
Number Of Sites
2
Number Of Participants
5

Sites

Site Name
Cliniques Universitaires Saint-Luc
Department Name
#1001: Hematology – Day Hospital
Contact Person Name
An Van Damme
Site Name
Universitair Ziekenhuis Gent
Department Name
#1000: Pediatric Hemato-Oncology
Contact Person Name
Leen Willems
Contact Person Email
Leen.Willems@uzgent.be

France

Earliest CTIS Part Ii Submission Date
30-09-2025
Latest Decision Or Authorization Date
17-04-2026
Processing Time Days
200
Number Of Sites
9
Number Of Participants
22

Sites

Site Name
Centre Hospitalier Universitaire De Toulouse
Department Name
#1106: Département de médecine vasculaire - Hôpital Rangueil
Contact Person Name
Maeva SEVERINO
Site Name
Centre Hospitalier Universitaire De Toulouse
Department Name
#1106: Département Dermatologie
Contact Person Name
Maeva SEVERINO
Site Name
Centre Hospitalier Universitaire De Dijon
Department Name
#1104: Département de Génétique Médicale
Contact Person Name
Bertille BONNIAUD
Contact Person Email
bertille.bonniaud@chu-dijon.fr
Site Name
Centre Hospitalier Universitaire De Montpellier
Department Name
#1105: Service de Médecine Vasculaire
Contact Person Name
Didier BESSIS
Contact Person Email
d-bessis@chu-montpellier.fr
Site Name
Centre Hospitalier Universitaire D'Angers
Department Name
#1103: Service de Dermatologie
Contact Person Name
Ludovic MARTIN
Contact Person Email
lumartin@chu-angers.fr
Site Name
Hopital Necker Enfants Malades
Department Name
#1101: Centre d’investigation clinique
Contact Person Name
Guillaume CANAUD
Contact Person Email
Guillaume.canaud@inserm.fr
Site Name
Centre Hospitalier Regional Universitaire De Tours
Department Name
#1102: Hôpital Clocheville, Département de Médecine Pédiatrique
Contact Person Name
Annabel MARUANI
Contact Person Email
annabel.maruani@univ-tours.fr
Site Name
Centre Hospitalier Regional Universitaire De Tours
Department Name
#1102: Hôpital Bretonneau département de médecine adulte
Contact Person Name
Annabel MARUANI
Contact Person Email
annabel.maruani@univ-tours.fr
Site Name
Hospices Civils De Lyon
Department Name
#1100: Service imagerie hôpital Femme mère et enfant
Contact Person Name
Laurent GUIBAUD
Contact Person Email
laurent.guibaud@chu-lyon.fr

Netherlands

Earliest CTIS Part Ii Submission Date
19-09-2025
Latest Decision Or Authorization Date
13-05-2026
Processing Time Days
236
Number Of Sites
1
Number Of Participants
5

Sites

Site Name
Radboud universitair medisch centrum Stichting
Department Name
1400: Department of Pediatrics
Contact Person Name
Barbara Sjouke
Contact Person Email
barbara.sjouke@radboudumc.nl

Sponsor

Primary sponsor

Full Name
Novartis Pharma AG
Organisation Type
Pharmaceutical company
Country Of Registered Address
Switzerland

Contract research organisations

Name
Veeda Clinical Research Limited
Responsibilities
Pharmacokinetic sample analysis
Name
IQVIA Limited
Responsibilities
ECG data capture
Name
Iqvia Rds Inc.
Name
Bioclinica Inc.
Responsibilities
Independent central imaging review and analysis
Name
Parexel International (IRL) Limited
Name
Icon Clinical Research Limited
Name
Syneos Health Inc.

Third parties

  • {"country":"India","full_name":"Veeda Clinical Research Limited","duties_or_roles":"Pharmacokinetic sample analysis","organisation_type":"Pharmaceutical company"}
  • {"country":"United States","full_name":"Scout Clinical","duties_or_roles":"Patient expense (travel, lodging) reimbursement.","organisation_type":"Hospital/Clinic/Other health care facility"}
  • {"country":"United States","full_name":"Iqvia Rds Inc.","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
  • {"country":"United Kingdom","full_name":"IQVIA Limited","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
  • {"country":"United States","full_name":"Jumo Health USA Inc.","duties_or_roles":"Patient recruitment and retention tools","organisation_type":"Hospital/Clinic/Other health care facility"}
  • {"country":"United States","full_name":"Bioclinica Inc.","duties_or_roles":"Independent central imaging review and analysis","organisation_type":"Laboratory/Research/Testing facility"}
  • {"country":"United Kingdom","full_name":"Adelphi Values Limited","duties_or_roles":"Participant embedded interviews vendor","organisation_type":"Pharmaceutical company"}
  • {"country":"United States","full_name":"Syneos Health Inc.","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
  • {"country":"United Kingdom","full_name":"IQVIA Limited","duties_or_roles":"ECG data capture","organisation_type":"Pharmaceutical company"}
  • {"country":"United States","full_name":"RWS Life Sciences Inc.","duties_or_roles":"PRO translations and licensing","organisation_type":"Pharmaceutical company"}
  • {"country":"Ireland","full_name":"Icon Clinical Research Limited","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
  • {"country":"United Kingdom","full_name":"Q Squared Solutions Limited","duties_or_roles":"","organisation_type":"Non-Pharmaceutical company"}
  • {"country":"France","full_name":"Kayentis","duties_or_roles":"eCOA, providing the electronic tablet for patients","organisation_type":"Non-Pharmaceutical company"}
  • {"country":"Ireland","full_name":"Parexel International (IRL) Limited","duties_or_roles":"","organisation_type":"Pharmaceutical company"}

Investigational products

Investigational Product Name
BYL719
Active Substance
ALPELISIB
Modality
Small molecule
Routes Of Administration
ORAL USE
Route
Oral
Authorisation Status
Authorized (prodAuthStatus=1)
Orphan Designation
Yes
Maximum Dose
250 mg

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